The present invention relates to novel and useful L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same, to processes for producing the same and to uses of the same as a cosmetic component or ingredient, antioxidant, radical scavenger, anti-inflammatory agent or elastase inhibitor.
There have heretofore been known L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diesters represented by the following formula (I) (International Publication No. WO 01/04114): 
The international publication discloses that the diester compounds are usable as a cosmetic ingredient, antioxidant, radical scavenger or anti-inflammatory agent.
However, the process as described in the said international publication suffers from the defects that the resultant L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diesters are difficult to crystallize, that the said diesters, even after being made crystalline, are difficult to be filtered, and that even the crystals obtained in any way are inferior in stability, and can be considered incomplete and defective in terms of a commercial-scale process. Therefore, there is strongly demanded a crystallization process for the L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diesters which process can eliminate such defects.
Under these circumstances, the present inventors conducted repeatedly extensive investigation, and as a result, found that the post-reaction treatment with use of 1-propanol and a solution mixture of 1-propanol with an organic solvent can yield L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diesters with enhanced crystallinity and improved filtrability and that the 1-propanol adduct obtained in this manner is excellent in stability. These findings, followed by further research work, have culminated into completion of the present invention.
The present invention relates to:
(1) L-Ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same (hereinafter referred to in some instances as xe2x80x9cCompoundsxe2x80x9d),
(2) L-Ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct or their pharmacologically acceptable salts of the same in the crystalline form,
(3) A process for producing L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct, characterized in that said process comprises subjecting a solution containing a L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester to extraction with an extraction solvent, distilling off the extraction solvent, and admixing the resultant residue with 1-propanol or a solution mixture of 1-propanol with an organic solvent to thereby allow crystallization,
(4) A process as described above under the item (3), wherein the said organic solvent is n-hexane, cyclohexane and/or petroleum ether,
(5) A process as described above under the item (3) or (4), wherein the said extraction solvent is chloroform, ethyl acetate or a solvent mixture thereof,
(6) Compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same,
(7) Cosmetic compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same,
(8) Antioxidant compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same,
(9) Radical scavenging compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same,
(10) Anti-inflammatory compositions, characterized in that said compositions comprise L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same, and
(11) Elastase inhibitory compositions, characterized in that said compositions comprise L-xcex1-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1 -propanol adduct or pharmacologically acceptable salts of the same.
Also, the present invention provides a method of enhancing the elastase inhibition, a method of suppressing erythema caused by ultraviolet radiation, a method of preventing suntan caused by ultraviolet radiation, a method of skin beauty care, skin whitening care or skin-crease prevention, a method of preventing oxidation, a method of radical scavenging and a method of treating inflammatory diseases.
Furthermore, the present invention provides uses of L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct or pharmacologically acceptable salts of the same in the manufacture of cosmetics, antioxidants, radical scavengers or elastase inhibitors.
The process for producing L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diesters as claimed in the above-mentioned international publication, comprising use of ethanol in the purification step, yields the crystallized ethanol adducts of said diesters, which are considered to be freed of the alcohol (dealcoholization) by subsequent drying under reduced pressure.
Intensive investigation into these phenomena led to the finding that use of an alcohol can allow L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diesters to crystallize through addition of the alcohol. In the crystallization and production processes for these compounds, an alcohol may be used solely, but is preferably used in combination with one or two or more of n-hexane, cyclohexane and petroleum ether. It was found out that these crystalline alcohol adducts are freed of the alcohol (dealcoholization), when dried at about 60xc2x0 C. under reduced pressure, but are held intact in the form of an alcohol adduct consisting of 1 mole of L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester and 1 mole of an alcohol, when dried at a temperature in the neighborhood of 30xc2x0 C. Among these alcohols, 1-propanol or 1-butanol can afford the best crystallinity to the adduct products, whereas 2-propanol has the defect of inferior production yields since L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diesters are more soluble in it. It is added that methanol and butanol are not desirable in terms of toxicity and disagreeable odor, respectively. Comparison between ethanol and 1-propanol adducts led to the finding that 1-propanol adduct is by far superior to the ethanol one in thermal stability.
The pharmacologically acceptable salts of the present invention are exemplified by their alkali metal salts, such as their sodium and potassium salts, and their alkaline earth metal salts, such as their calcium and magnesium salts, and may include any miscellaneous salts, only if they are pharmacologically acceptable.
The L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester.1-propanol adduct of the present invention can property be synthesized, for example, by the following synthetic procedure or any other procedures similar to the same:
Maleic acid monotocopherol and ascorbic acid having the hydroxy groups protected at the 5 and 6 positions can be reacted in a highly polar solvent in the presence of a base, such as alkali carbonate compounds or triethylamine to effect esterification by the mixed acid anhydride method, followed by removal of the protective groups with an acid to give a L-ascorbic acid-2-O-maleic acid-xcex1-tocopherol diester mainly having an ester linkage at the 2 position of ascorbic acid. In this case, examples of the highly polar solvent include dimethylsulfoxide (DMSO), dimethylformamide (DMF), acetonitrile, etc., while the alkali carbonate compounds include, for example, sodium carbonate and potassium carbonate. A solution containing a diester compound as obtained by this manner is subjected to extraction with an extraction solvent, such as chloroform and ethyl acetate, and after distilling off the extraction solvent, the resultant residue is admixed with 1-propanol or a solution mixture of 1-propanol with one or two or more of n-hexane, cyclohexane, petroleum ether, etc. to allow the Compound to crystallize.
The Compound as obtained by this procedure can be converted into its pharmacologically acceptable salts by the conventionally known methods. The conversion into such salts may be effected after isolation from the reaction solution or directly without such isolation.
Maleic acid monotocopherol, which is a starting compound for the Compounds can be synthesized by the procedure as described in International Application No. PCT/JP98/05765 or those similar to the same.
Ascorbic acid having protective groups on the hydroxyl groups at the 5 and 6 positions, which is another starting compound, can be synthesized by the known procedures, such as those as described in JP-B-2-44478 and JP-B-5-23274, or those similar to the same. The protective groups for the hydroxyl groups at the 5 and 6 positions of ascorbic acid include, for example, acyl groups such as isopropylidene and benzylidene groups, with the isopropylidene group being commonly used. These protective groups can be removed easily by acidifying the reaction solution. On the occasion of such acidification, there can be utilized, for example, inorganic acids, such as hydrochloric acid, phosphoric acid and sulfuric acid, and organic acids, such as acetic acid and citric acid.
The Compounds, which possess anti-inflammatory activity, antioxidant activity, radical scavenging activity and elastase inhibitory activity, are specifically intended for use in the method of suppressing rubedo caused by ultraviolet radiation, method of preventing sun tanning caused by ultraviolet radiation and methods of skin beautification, skin whitening (prevention of deposition of melanin pigments which causes blotches, freckles, etc. and others) and crease prevention as well as in the stabilization of miscellaneous cosmetic ingredients, and consequently can suitably be added to cosmetics, such as creams, lotions and skin lotions.
In formulating the Compounds into cosmetics, there can suitably be added various ingredients which are ordinarily used for cosmetics. Such ingredients may include, for example, nicotinic acids, such as nicotinic acid, nicotinamide and benzyl nicotinate, vitamin As, such as retinol, retinoyl acetate and vitamin A oils, vitamin B2s, such as riboflavin, riboflavin acetate and flavin adenin dinucleotide, vitamin B6s, such as pyridoxine hydrochloride and pyridoxine dioctanoate, vitamin Cs, such as L-ascorbic acid, sodium L-ascorbic acid-2-sulfate and L-ascorbyl dipalmitate, pantothenic acids, such as calcium pantothenate, pantothenyl ethyl ether, D-pantothenyl alcohol and acetylpantothenyl ethyl ether, vitamin Ds, such as cholecalciferol and ergocalciferol, vitamin Es, such as xcex1-tocopherol, tocopherol acetate, DL-xcex1-tocopheryl nicotinate and DL-xcex1-tocopheryl succinate, miscellaneous vitamins; amino acids, such as glycine, alanine, phenylalanine, valine, leucine, isoleucine, serine, threonine, asparagine, aspartic acid, aspartates, glutamine, glutamic acid, glutamates, lysine, methionine, cysteine, cystine, arginine, histidine, tryptophane, proline and hydroxyproline, N-acylated acidic amino acid salts, such as sodium N-coconut oil fatty acid-L-glutamate and diethyl N-palmitoyl-L-aspartate, acylated neutral amino acid salts, such as sodium lauroylmethyl-xcex2-alanine and coconut oil fatty acid succinotriethanolamine, pyrrolidonecarboxylic acid and its salts, amino acid derivatives, such as polyoxyethylenated hardened castor oil monopyroglutamate monoisostearate diester and coconut oil fatty acid -L-arginine ethyl ester-DL-pyrrolidonecarboxylate, oils, such as rice bran oil, peanut oil, palm oil, beef tallow, avocado fat, jojoba oil, lanolin, liquid paraffin, squalane, camauba wax, isostearyl alcohol, isostearyl palmitate and glyceryl tri-2-ethylhexanoate, polyhydric alcohols, such as glycerol, sorbitol, mannitol and 1,3-butylene glycol, polyhydric alcohol ethers, such as polyethylene glycol, mucic polysaccharides, such as collagen, sodium hyaluronate, sodium chondrotin sulfate and sodium dextran sulfate, antioxidants, such as p-hydroxyanisole and sodium erythorbate, cellulose derivatives, such as carboxyvinyl polymer, carboxymethylcellulose and hydroxypropyl methylcelluolose, surfactants, such as sodium stearylsulfate, diethanolamine cetylsulfate, cetyl trimethylammonium saccharin, isostearyl polyethylene glycol, diglyceryl isostearate and phospholipids, preservatives, such as ethylparaben, propylparaben and butyl-paraben, anti-inflammatory agents, such as hinokitiol, salicylic acid derivatives, glycyrrhizinic acid derivatives, glycyrrhetic acid derivatives, allantoin and zinc oxide, miscellaneous pH regulating agents, buffers, perfumes and coloring agents.
In cases where the Compounds are used in cosmetics, they are normally formulated in a proportion of about 0.001 to 5 (w/w) %, preferably about 0.005 to 2 (w/w) %, although such proportion may be varied depending upon the type of the Compounds, the type of a cosmetic to be processed through formulation and the purpose of formulation.
The Compounds exhibit anti-inflammatory activity as described in the above, and the particular inflammatory disorders to be treated with the Compounds may include, for example, hemorrhoids, chronic rheumatoid arthritis, rheumatism deformans, spondylitis deformans, arthritis deformans, low back pain, onset of gout, acute otitis media, cystitis, prostatitis, odontalgia, conjunctivitis, keratitis, iridocyclitis, uveitis and sinusitis.
The Compounds may suitably be usable orally or parenterally as an anti-inflammatory agent, and can be processed into any dosage forms, such as solid pharmaceutical preparations being exemplified by tablets, granules, powders, capsules, etc. or liquid pharmaceutical preparations being exemplified by injections, ophthalmic solutions, etc., by the conventionally known processes. A variety of ordinarily used additives or pharmaceutic aids, such as excipients, binders, thickeners, dispersing agents, reabsorption promoters, buffers, surfactants, solubilizing agents, preservatives, emulsifying agents, tonicity agents, stabilizing agents and pH regulating agents, may suitably used in such dosage forms.
In using the Compounds as an anti-inflammatory agent, the dose may be varied depending upon the body weight and age of a patient, the sort and conditions of a disorder to be treated and the method of administration, and they may desirably be administered to adult patients at doses ranging from about 1 mg to about 30 mg once a day in the case of injections, and at doses ranging from about 1 mg to about 100 mg each time and several times a day in the case of pharmaceuticals for internal use. In the case of ophthalmic solutions, an ophthalmic solution of a concentration varying from about 0.01 to 5 (w/v) % is preferably instilled or applied topically to the eye of adult patient in several drops each time and several times a day.
The anti-inflammatory agents comprising the Compounds may be incorporated with any other anti-inflammatory agents or different types of active agents, unless they are contradictory to the purposes of the present invention.